BioWorld International Correspondent
LONDON - A potential new trigger for the development of male infertility has been identified from work on mice, by scientists who originally set out to study the formation of new blood vessels around tumors.
The serendipitous discovery, which shows that a molecule called JAM-C is critical for the development of mature sperm cells, will provide important information for those trying to understand the molecular causes of male infertility.
Ralf Adams, head of the vascular development laboratory at the Cancer Research UK London Research Institute, said: “We discovered JAM-C had a similar pattern of expression in human sperm to that found in mice. This suggests that defects in JAM-C could contribute to male infertility in humans. It will be important for scientists working in this area to investigate this further.”
Adams and his colleagues, including collaborators in Germany and Switzerland, report their work in a letter to Nature, titled “Spermatid differentiation requires the assembly of a cell polarity complex downstream of junctional adhesion molecule-C.”
The team had been investigating the role of JAM-C in angiogenesis and decided to make a knockout mouse that lacked functional JAM-C. Only about 40 percent of those animals survived the postnatal period.
Emma Knight, science information officer at Cancer Research UK, told BioWorld International, “To their surprise, when the researchers tried to breed these mice, they found that the males were infertile.”
Sperm cells develop in the testes and undergo a series of changes until they are mature and viable. They begin life as round cells, and as they mature they elongate and develop a tail. Defects at any stage of that process can prevent the cells from maturing and lead to male infertility.
Tests on the infertile mice showed that the sperm cells remained round rather than becoming elongated, as they should be.
Adams and his group went on to look at whether the levels of JAM-C changed as sperm cells matured. They noticed that the molecule was widely distributed in round sperm cells, but was present at higher concentrations on one side of the cell. As the cells matured, JAM-C became localized to the heads of elongated sperm.
Knight said: “These findings led the team to believe that JAM-C might have a role in defining which end of the sperm cell becomes the head.”
To test that theory, they went on to study the cellular distribution of molecules known to regulate which end becomes the head. They found that those molecules, which include Par6, Cdc42 and PKC-lambda, had similar distributions to JAM-C during sperm development.
In order to find out if those proteins played similar roles in human spermiogenesis, Adams’ team also studied where JAM-C, Par6 and Cdc42 could be found in sections of human testes. They found that JAM-C was present in human spermatids (precursors to sperm cells), and that it was found on only one side of those cells - as in mice.
Patterns of distributions of both Par6 and Cdc42 also were similar to those seen in mice. Writing in Nature, the authors said: “Therefore, it seems that the role of JAM-C and downstream cell polarity regulators may be conserved and relevant for human reproduction.”
In their paper, they concluded: “Our results show that JAM-C is required for the polarization of round spermatids, which we attribute to its role in the recruitment of a cell polarity complex. . . It seems feasible that genetic defects, as well as other factors interfering with normal JAM-C function in the human reproductive system, could lead to male infertility.”
Knight said that Cancer Research UK hoped that researchers working on infertility would take the discovery forward. “It would be interesting, for example, to try to find out whether men attending infertility clinics have any mutations in the gene encoding JAM-C, in comparison with the general population,” she said. “If this turns out to be the case, further research into the role of JAM-C in the cell may lead to the development of new drugs that could treat men with this type of infertility.”